Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease that leads to the destruction of diarthrodial joints. Currently, there is no cure for RA. Available antirheumatic drugs exhibit variable therapeutic efficacy and are frequently associated with significant toxicities that may be due to their systemic distribution and lack of tissue-specificity to arthritic joints. To overcome these problems, we propose to develop a novel water-soluble polymeric delivery system that will selectively deliver and release drugs at the sites of multiple inflammatory joints. Such delivery system would provide superior therapeutic efficacy and greatly reduced side effects. A potent glucocorticoid, dexamethasone (Dex), will be used as the model drug in this study. Angiogenesis, increased vascular permeability (leaky vasculature), leukocytes infiltration and synovial lining hyperplasia will facilitate the selective delivery and retention of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-Dex conjugate to arthritic joints. The tissue-specific release of Dex in arthritic joint tissues will be achieved by conjugating Dex to HPMA copolymer carrier via a pH-sensitive hydrazone bond that can be specifically cleaved under the acidic conditions found in arthritis joint tissues (acidosis) and in acidic lysosomal compartments of cells of synovial tissues. In the proposed experiments, we will evaluate the influence of various factors (e.g. severity of the disease, physicochemical characteristics of the polymer drug conjugate and the presence of different synovial cell types) on delivery system selectivity and drug release profiles. The full therapeutic potential of the delivery system will be tested after optimization of the conjugate design. A detailed safety profile of the delivery system will then be determined. Lay language: This novel polymeric drug delivery system can selectively deliver dexamethasone to multiple inflammatory joints of rheumatoid arthritis patients. It could be further adapted to other anti-rheumatic drugs to achieve inflammatory joint specificity. Eventually, this novel delivery system would lead to improved efficacy and safety profiles for treatment of rheumatoid arthritis and other inflammatory joint disorders.